Mucoadhesive liposomal delivery system synergizing anti-inflammation and anti-oxidation for enhanced treatment against dry eye disease.

Dry eye disease (DED) is a common and frequent ocular surface disease worldwide, which can cause severe ocular surface discomfort and blurred vision. Inflammation and reactive oxygen species (ROS) play decisive roles in the development of DED. However, existing treatments usually focus on anti-inflammation while ignore the role of ROS in DED. Ever worse, the clinical preparations are easily cleared by nasolacrimal ducts, resulting in poor therapeutic effect. To circumvent these obstacles, here we designed a phenylboronic acid (PBA) modified liposome co-loading immunosuppressant cyclosporin A (CsA) and antioxidant crocin (Cro). The CsA/Cro PBA Lip achieved mucoadhesion through the formation of covalent bonds between PBA and the sialic acid residues on mucin, and consequently improved the retention of drugs on the ocular surface. By inhibiting ROS production and blocking NF-κB inflammatory pathway, CsA/Cro PBA Lip successfully promoted the healing of damaged corneal epithelium, eventually achieving the goal of relieving DED. CsA/Cro PBA Lip is proven a simple yet effective dual-drug delivery system, exhibiting superior antioxidant and anti-inflammatory effects both in vitro and in vivo. This approach holds great potential in the clinical treatment of DED and other related mucosal inflammations.

Depriving Tumor Cells of Ways to Metastasize: Ferroptosis Nanotherapy Blocks Both Hematogenous Metastasis and Lymphatic Metastasis.

Blood and lymph are two main pathways of tumor metastasis; however, hematogenous metastasis and lymphatic metastasis are difficult to inhibit simultaneously. Ferroptosis provides a new breakthrough for metastasis inhibition, but how to effectively trigger ferroptosis in tumor cells remains a major challenge. Metastatic tumor cells are prone to ferroptosis in blood, while they may be protected from ferroptosis in lymph. In this study, a nanoplatform DA/RSL3 was constructed for the intracellular codelivery of the polyunsaturated arachidonic acid (AA) and the GPX4 inhibitor RSL3, which could not only induce ferroptosis but also alleviate ferroptosis resistance. As a result, DA/RSL3 effectively triggered ferroptosis in tumor cells, thereby impairing the ability of tumor cells to metastasize in both blood and lymph. Furthermore, a fucoidan blocking strategy was proposed to maximize the efficacy of DA/RSL3. Fu+DA/RSL3 showed excellent efficacy in 4T1 tumor-bearing mice. This ferroptosis nanotherapy is promising for metastatic cancer treatment.

Micellar nanoparticles inhibit breast cancer and pulmonary metastasis by modulating the recruitment and depletion of myeloid-derived suppressor cells.

Myeloid-derived suppressor cells (MDSCs) are notorious for their pathological characteristics of immunosuppression and their promoting effect on cancers. They can induce the formation of pre-metastatic niche (PMN) characterized by inflammation, immunosuppression and vascular leakage, and promote pulmonary metastasis of breast cancer. Herein, a tumor targeting c(RGDfk) peptide modified low molecular-weight-heparin-all-trans-retinoic-acid (LMWH-ATRA) micellar nanoparticle loaded with chemotherapeutic drug doxorubicin (DOX) and immune adjuvant α-galactosylceramide (αGC) (RLA/DOX/αGC NP) was developed. The hydrophilic segment LMWH inhibited the recruitment of MDSCs by competitively binding with P-selectin on the surface of vascular endothelial cells (VECs), while the hydrophobic segment ATRA promoted the depletion of MDSCs by inducing their differentiation. Through the modulation of MDSCs, micelles can significantly improve the inflammatory and immunosuppressive microenvironment of the lung and tumor sites, and inhibit the formation of PMN. Not only this, the micelles also produced a synergistic effect with αGC, which effectively improved the anti-tumor immunity of tumor bearing mice and provided a promising therapeutic strategy for breast cancer and pulmonary metastasis.

Spatially targeting and regulating tumor-associated macrophages using a raspberry-like micellar system sensitizes pancreatic cancer chemoimmunotherapy.

Dense stroma and an immunosuppressive microenvironment severely hamper the antitumor therapeutic results of pancreatic cancer. Tumor-associated macrophages (TAMs) support the proliferation and invasion of tumor cells and contribute to the information of the immunosuppressive tumor microenvironment (TME). The repolarization of TAMs activates the antitumor immune response and sensitizes chemotherapy. Nevertheless, the difference in distributed mode between TAMs and tumor cells in tumor turns out to be an obstacle for dual targeting. To repolarize TAMs and elevate the chemoimmunotherapy outcome against pancreatic cancer, co-loading the TME responsive micellar system with gemcitabine (GEM) and PI3K inhibitor wortmannin (Wtmn) was used to dual target TAMs and tumor cells. GEM conjugated dendritic poly-lysine DGL (GD) nanoparticles were linked to polycaprolactone-polyethylene glycol micelles encapsulated with Wtmn (PP/Wtmn) via a cathepsin B (CTSB) substrate peptide to obtain raspberry-like GD@PP/Wtmn micelles. Upon arrival at the TME, GD was released in response to highly expressed CTSB, allowing deep penetration of the tumor and overcoming of the stromal barrier, while PP/Wtmn remained in the perivascular area where TAMs abundantly resided. By inhibiting the PI3K pathway, the M2-like TAMs were repolarized into M1-like TAMs and then activated antitumor immunity, further synergizing with GEM to suppress tumor growth. This tumor and TAMs dual targeting nanoplatform provides an alternative approach to sensitize chemoimmunotherapy against pancreatic cancer.

Fucoidan-functionalized activated platelet-hitchhiking micelles simultaneously track tumor cells and remodel the immunosuppressive microenvironment for efficient metastatic cancer treatment.

Tumor metastasis is responsible for most mortality in cancer patients, and remains a challenge in clinical cancer treatment. Platelets can be recruited and activated by tumor cells, then adhere to circulating tumor cells (CTCs) and assist tumor cells extravasate in distant organs. Therefore, nanoparticles specially hitchhiking on activated platelets are considered to have excellent targeting ability for primary tumor, CTCs and metastasis in distant organs. However, the activated tumor-homing platelets will release transforming growth factor-ß (TGF-ß), which promotes tumor metastasis and forms immunosuppressive microenvironment. Therefore, a multitalent strategy is needed to balance the accurate tumor tracking and alleviate the immunosuppressive signals. In this study, a fucoidan-functionalized micelle (FD/DOX) was constructed, which could efficiently adhere to activated platelets through P-selectin. Compared with the micelle without P-selectin targeting effect, FD/DOX had increased distribution in both tumor tissue and metastasis niche, and exhibited excellent anti-tumor and anti-metastasis efficacy on 4T1 spontaneous metastasis model. In addition, due to the contribution of fucoidan, FD/DOX treatment was confirmed to inhibit the expression of TGF-ß, thereby stimulating anti-tumor immune response and reversing the immunosuppressive microenvironment. The fucoidan-functionalized activated platelets-hitchhiking micelle was promising for the metastatic cancer treatment.

Platelet­derived growth factor­BB mediates pancreatic cancer malignancy via regulation of the Hippo/Yes­associated protein signaling pathway.

Platelet­derived growth factor (PDGF) is a potent mitogen and chemoattractant that serves a role in the development of several types of solid cancer, and abnormal PDGF activity has been reported in numerous human tumors. Tumor­derived PDGF ligands are considered to act in either a paracrine or autocrine manner, serving roles in the phosphorylation of receptors on tumor and stromal cells in the tumor microenvironment. Despite the well­established association between PDGF and tumor progression, the precise mechanisms of autocrine PDGF signaling in pancreatic tumor cells remain elusive. Therefore, the present study aimed to analyze the influence of PDGF­BB in pancreatic cancer. Pancreatic adenocarcinoma BxPC­3 cells were cultured and treated with recombinant human PDGF­BB in vitro. Cell proliferation was tested using an MTT assay. Cell apoptosis was measured using flow cytometry. Tumor cell migration and invasion were examined via wound­healing and Transwell assays, respectively. The expression and subcellular localization of Yes­associated protein (YAP) was determined using western blotting and immunofluorescence. The transcriptional activity of target genes was tested using a luciferase assay and reverse transcription­quantitative PCR. The present study revealed that PDGF­BB significantly promoted cell proliferation in pancreatic adenocarcinoma BxPC­3 cells and enhanced the aggressiveness of this cell line, as demonstrated by Transwell and wound­healing assays. Anoikis resistance is an important mechanism by which metastatic cells avoid apoptosis when detaching from adjacent cells or the extracellular matrix. PDGF­BB treatment inhibited anoikis under anchorage­independent conditions. Mechanistic experiments revealed that PDGF­BB promoted the upregulation and activation of the transcriptional coactivator YAP, an effector of the Hippo signaling pathway. RhoA or protein phosphatase­1 (PP­1) inhibition partially abolished the accumulation and activation of YAP, suggesting PDGF­BB­mediated YAP dephosphorylation and transactivation via the RhoA/PP­1 cascade. Pharmacologic inhibition of the PDGF receptor directly downregulated YAP activity and the expression levels of downstream genes. Furthermore, verteporfin, a small molecular inhibitor of the Hippo/YAP signaling pathway, partially reversed the effects of PDGF­BB on cell proliferation, anoikis resistance and cell migration. In conclusion, the present study revealed that the Hippo/YAP signaling pathway may be involved in the tumor­promoting activity of PDGF­BB in pancreatic cancer.

The association between sleep duration, napping, and stroke stratified by self-health status among Chinese people over 65 years old from the China health and retirement longitudinal study.

PURPOSE: Stroke is a major cause of death in China. This study aimed to investigate the association between sleep duration (nighttime sleep and daytime napping) and stroke in elderly Chinese individuals with self-reported health status. METHODS: A total of 4785 Chinese adults over 65 years from the 2011 China Health and Retirement Longitudinal Study (CHARLS) were included. Binary logistic regression was used to estimate odds ratios and 95% confidence intervals of the association between sleep duration and stroke stratified by self-reported health status. RESULTS: A significant association between short sleep duration (< 7 h per day) and the risk of stroke (aOR = 2.05; 95% CI 1.31-3.19), after controlling for sociodemographic characteristics, lifestyle factors, health status, and comorbidities. There was no significant association between short and long sleep duration and stroke in the individuals who reported good general health status. However, in individuals who reported poor health status, short sleep duration (aOR = 2.11; 95% CI 1.30-3.44) and long sleep duration (aOR = 1.86; 95% CI 1.08-3.21) were significantly associated with increased risk of stroke, compared with normal sleep duration (7-8 h per day). Disability was significantly associated with stroke in both self-reported good and poor health groups. Rural residence was significantly associated with a lower risk of stroke among individuals who reported poor health status. CONCLUSIONS: Both short and long sleep duration were significantly associated with stroke among individuals who reported poor health. Stroke prevention should be focused on elderly individuals who believe that they have health problems.

Extracellular histones and xenotransplantation.

Xenotransplantation may be an alternative source of organs for patients with end-stage organ failure, but problems remain to be overcome. Five factors that are problematic are (a) a sustained systemic inflammatory response in the xenograft recipient, (b) thrombotic microangiopathy and disseminated intravascular coagulation, (c) ischemia-reperfusion injury, (d) complement activation, and (e) vascular endothelial cell injury. In xenotransplantation, histones, which are positively charged proteins, are released into the extracellular space from damaged and activated cells, cause cell and tissue damage, and act as danger/damage-associated molecular patterns (DAMPs) that mediate inflammation, coagulation disorders, an immune response, and cytotoxicity. We have previously demonstrated that serum histones increase after pig-to-baboon organ transplantation and infection. Treatment of the recipient with tocilizumab (interleukin-6 receptor blockade) reduces the level of serum histones and C-reactive protein. In this review, the potential role of extracellular histones in xenotransplantation is discussed, and we briefly summarize the relationship between extracellular histones and the inflammatory response, coagulation dysfunction, ischemia-reperfusion injury, the complement system, and vascular endothelial cell injury.